Glioblastomas are extremely complex and malignant neoplasms. We have taken several approaches to understand and identify, at a molecular level, the underlying mechanisms that translate into the malignant behavior of these tumors. 1. Immunohistochemical analysis of the p53 protein showed a heterogeneous pattern of subcellular compartmentalization of glioblastomas. Tumors with one single wild type allele of p53 and deletion of chromosome 17 display predominantly cytoplasmic, nuclear, or both cytoplasmic and nuclear reactivity. Furthermore, tumors with mutations in the same codon of p53 display very different staining patterns. These data suggest that the microenvironment of a particular tumor is important in determining the subcellular localization of p53. 2. Twenty tumors were analyzed for collagenase IV and Timp-2 expression. Both these genes were generally overexpressed in glial tumors compared to the normal human. brain. 3. Eight matched pairs of primary and recurrent tumors were analyzed for allelic deletions on chromosomes 10 and 17. The data clearly demonstrated additional genetic abnormalities in recurrent tumors, which included amplification of the alphaPDGRF gene, point mutations of the p53 gene and overexpression of collagenase and Timp-2. 4. Analysis of metastatic brain tumors showed chromosome 17p deletions and/or p53 mutations in 60% of the tumors. Our data support the concept that p53 gene alterations may contribute to the metastatic spread in certain types of cancers. 5. A region of homozygosity on chromosome 10q was identified in primary glial tumors as well as in brain metastases suggesting the presence of a gene(s) on chromosome 10q that plays a role not only in glial tumorigenesis but also in homing of certain types of tumors to the brain.